At present no tractable animal model for HIV-1 induced immunodeficiency of man exists. HIV-1 readily establishes infections of chimpanzees but no disease is induced. Our current knowledge about HIV-1 pathogenesis in vivo derives from retrospective clinical analyses and biopsies of lymphoid tissues collected from infected individuals. Studies of the closely related SIV and its infection of Asian macaques have provided useful information about the sites and kinetics of primate lentivirus infections in vivo. SIV/HIV chimeric viruses (SHIVs), carrying several HIV-1 genes, have been constructed and used to monitor the roles of the HIV-1 envelope glycoprotein in infected animals. Highly pathogenic SHIVs have recently been obtained, which induce a rapid (within 2 to 3 weeks of inoculation), irreversible depletion of CD4+ T lymphocytes in the peripheral blood of acutely infected rhesus monkeys. To more fully assess these unusual systemic effects, individual rhesus monkeys were sacrificed on days 3, 5, 7, 10, 14, and 21 post infection and specimens were collected from a variety of lymphoid tissues (lymph nodes, thymus and spleen) and gastrointestinal tract and examined by DNA and RNA PCR, in situ hybridization (ISH) and immunohistochemical (IHC) assays. In addition, the lymphoid tissues were evaluated by fluorescence activated cell sorting (FACS). Both FACS and IHC analyses indicated that CD4+ T cell loss from lymphoid tissues began between days 10 and 14 post infection and was, for the most part, systemically synchronous. Virus producing cells peaked on day 10 in the T cell rich regions of lymph nodes and on day 14 in the thymic medulla and PBMC. In situ TUNEL assays revealed the accumulation of apoptotic cells during the second week of infection in both lymph nodes and thymus, which co-localized, to a large extent, to sites of both virus replication and CD4+ T lymphocyte loss.